In early reports 1,2 we identified a population of cells within the pontine reticular formation (PRF) of the rat with activity highly correlated with the theta rhythm of the hippocampus. In subsequent studies 3,4 we showed that electrical stimulation of this same PRF region produced pronounced hippocampal theta. In mapping the brainstem for its synchronizing (theta) effects on the hippocampus, we also demonstrated that stimulation of the median raphe (MR) nucleus desynchronized the hippocampal EEG.4 We proposed that the PRF (predominantly nucleus pontis oralis) and the MR are directly involved in generating states of hippocampal synchronization and desynchronization, respectively. Our most recent work 5-9 has concentrated on anatomically defining PRF and MR pathways to the medial septum-vertical limb of the diagonal band nuclei (MS-DBv) - - the site of the pacemaking cells that directly control the hippocampal EEG. In brief, we have demonstrated pronounced projections from the MR to the MS-DBv, but very few direct projections from the PRF to the MS-DBv. We now suggest that the supramammillary nucleus (SUM) may serve as an important link between the PRF and the MS-DBv involved in hippocampal theta generation. The proposed studies are designed to precisely define brainstem to septohippocampal systems involved in controlling states of hippocampal synchronization and desynchronization. Specifically, we intend to examine: (1) the relationship of unit activity in the PRF, MR and SUM to the hippocampal EEG in the behaving rat; (2) the effects of cellular destruction of these same three nuclei on the hippocampal EEG; (3) afferents to the PRF; (4) PRF projections to the SUM; (5) MR and SUM projections to ChAT-containing cells of the MS-DBv and (6) the distribution of 5-HT and non 5-HT median raphe fibers to the MS-DBv. Several recent reports 10-17 have shown that hippocampal long term potentiation (LTP) is optimally induced with stimulation at theta frequency and it has been suggested that the theta rhythm may represent an endogenous system for memory.10,11,14-18 To our knowledge, our laboratory is the only one that is currently examining the source(s) for the generation of the theta rhythm within the brainstem. If, as indicated, theta proves to be critically involved in memory, we believe that it is important to fully understand neural mechanisms responsible for its generation.